Currently, the treatment of diabetes, both type 1 diabetes and type 2 diabetes, relies to an increasing extent on the so-called intensive insulin treatment. According to this regimen, the patients are treated with multiple daily insulin injections comprising one or two daily injections of a long acting insulin to cover the basal insulin requirement supplemented by bolus injections of a rapid acting insulin to cover the insulin requirement related to meals.
Insulin is a 51 amino acid peptide hormone produced in the islets of Langerhans in the pancreas. Its primary function, acting as a monomer, is to facilitate the transport of glucose molecules across the cell membranes of adipose and muscle tissue by binding to and activating a transmembrane receptor.
A distinctive property of insulin is its ability to associate into hexamers, in which form the hormone is protected from chemical and physical degradation during biosynthesis and storage. X-ray crystallographic studies on insulin show that the hexamer consists of three dimers related by a 3-fold axis of rotation. These dimers are closely associated through the interaction of two zinc ions at its core positioned on the 3-fold axis. Two hexamers of insulin may associate into dodecamer insulin complexes, which may associate into even larger complexes, eg. two, three or four dodecamers forming complexes together.
The presence of zinc in insulin formulations increases the tendency of insulin self-association. The more zinc present in the formulation the higher tendency for the insulin to self-associate into hexamers or even larger insulin complexes depending on the conditions. As absorption from the injection site through the capillary wall is negatively correlated with size of the assembly (monomers are absorbed faster than dimers, which in turn are absorbed faster than hexamers etc.) formation of larger insulin complexes will extent the clinical properties of the insulin towards a basal profile.
When human insulin is injected into the subcutis in the form of a high-concentration pharmaceutical formulation it is self associated to primarily hexamers, and here dissociation into monomers is relatively slow. Hexamers and dimers of insulin are slower to penetrate capillary wall than monomers. Therefore when injecting basal insulin it is desired to have as few monomers present as possible.
International patent application WO 99/24071 discloses a method for preventing self-association of insulin into dimers, tetramers and hexamers. The self-association is prevented by the presence of histidine.
International patent application published under number WO 2007/041481 concerns formulation comprising insulin selected from the group consisting of intermediate acting and a long acting insulin with an effective amount of a chelator and an acidifying agent to enhance the rate or amount of uptake by a patient. The chelator may be selected among a number of compounds, e.g. EDTA or citric acid. It is believed that the chelator pulls the zinc away from the insulin, thereby favouring the monomeric form of the insulin over the hexameric form.
It would be desirable to have a soluble formulation of insulin where the insulin is present in the dodecamer form.